Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.

Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.

Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.

Mentions:
When comparing the effects of i.v. rt-PA treatment after 3 h MCAO in non-anticoagulated mice and in mice pretreated with oral warfarin to an INR of approximately 3, warfarin pretreatment vastly increased the amount of HT (9.2±3.2 µl vs. 2.8±1 µl, n = 6 in both groups, p<0.05) (Fig. 2A). There was a tendency, however non-significant, towards a more severe neurological deficit in warfarin-treated mice that received rt-PA as compared to mice without prior warfarin intake that received rt-PA (median 5 vs. 4.5, p = 0.1970 [Gaussian approximation]) (Fig. 2B). One mouse receiving rt-PA without prior warfarin treatment had to be excluded due to a failure of i.v. substance application and was substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 4.36 for this comparison providing a statistical power of 99%.

Mentions:
When comparing the effects of i.v. rt-PA treatment after 3 h MCAO in non-anticoagulated mice and in mice pretreated with oral warfarin to an INR of approximately 3, warfarin pretreatment vastly increased the amount of HT (9.2±3.2 µl vs. 2.8±1 µl, n = 6 in both groups, p<0.05) (Fig. 2A). There was a tendency, however non-significant, towards a more severe neurological deficit in warfarin-treated mice that received rt-PA as compared to mice without prior warfarin intake that received rt-PA (median 5 vs. 4.5, p = 0.1970 [Gaussian approximation]) (Fig. 2B). One mouse receiving rt-PA without prior warfarin treatment had to be excluded due to a failure of i.v. substance application and was substituted to the operator in a blinded fashion. Post-hoc statistical power analyses showed an effect size (Cohen's d) of 4.36 for this comparison providing a statistical power of 99%.

Bottom Line:
To achieve effective anticoagulation, warfarin was administered orally.The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.

Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.

Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.

Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.